Is BUB1 p.Thr306Pro (c.916A>C) pathogenic?

BUB1 p.Thr306Pro (c.916A>C) is classified Uncertain significance in BUB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-28). AlphaMissense: likely benign (0.0715); Very rare (popmax 0.00249%, eas).

How common is BUB1 p.Thr306Pro (c.916A>C) in the general population?

BUB1 p.Thr306Pro (c.916A>C) is very rare (popmax 0.00249%, eas) (gnomAD).

What do computational predictors say about BUB1 p.Thr306Pro (c.916A>C)?

AlphaMissense predicts likely benign (score 0.0715) — an in-silico prediction, not a clinical call.

BUB1 p.Thr306Pro

c.916A>C · rs1163922652 · VCV3135597

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0715 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00249%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0715	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -9.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.13	phastCons 0.002
Regional constraint	o/e 0.90	unconstrained · MANE · 40 kb · p 0.00043 · regional, not allelic
Overall
CADD	13.26	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00249% East Asian · 1/40,158 alleles

Overall 0.000266% 4/1,504,704 alleles · very rare exomes 3/1,352,378 · genomes 1/152,326 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00522%	19,151
East Asiangrpmax	0.00249%	40,158

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: BUB1
Protein: p.Thr306Pro
Coding: c.916A>C
MANE Select: NM_004336
dbSNP: rs1163922652
Type: single nucleotide variant
Location: chr2:110666304 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.91 · 11 PDB
Residue 306: the 'disordered' region

Full BUB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BUB1 p.Thr306Ala Uncertain significance ★ ⚠ same residue
BUB1 p.Thr306Ile Uncertain significance ★ ⚠ same residue
BUB1 c.1698+1G>T Uncertain significance ★★ same type
BUB1 p.Ala281Thr Uncertain significance ★★ ⚠ same type
BUB1 p.Ala283Thr Uncertain significance ★★ ⚠ same type
BUB1 p.Ala499Val Uncertain significance ★★ ⚠ same type
BUB1 p.Ala502Ser Uncertain significance ★★ ⚠ same type
BUB1 p.Ala630Gly Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/bub1-p-thr306pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown